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Possible influencing the motor performance of developing rats by repeated administration of the NMDA receptor antagonist specific for NR2 subunit
Kozlová, Lucie ; Mareš, Pavel (advisor) ; Valeš, Karel (referee)
Nonspecific NMDA receptor antagonists induce hyperlocomotion in rats. The aim of this work is to determine whether the NMDA receptor antagonist specific for NR2 subunit exhibit similar negative effect as nonspecific antagonists. This subunit is predominant in the brain in the early postnatal period. The introduction summarizes the data on NMDA receptors and the development of rat. The experimental part deals with the action of a specific NMDA receptor antagonist Ro 25-6981 on motor performance of developing rats. Substance was repeatedly administered to rats at postnatal days 7 to 11. Spontaneous locomotion and motor performance of the animals were repeatedly tested up to adulthood by battery of tests appropriate for individual ages. Our research demonstrated that this substance does not have significant effect on motor system of laboratory rat and that it might be further tested as a possible age-bound antiepileptic drug.
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Automated monitoring of behaviour as a new paradigm in the research of depressive disorder
Revayová, Anna ; Valeš, Karel (advisor) ; Kubik-Zahorodna, Agnieszka (referee)
The rapid antidepressant effect of ketamine changed the direction of the research of potential antidepressants and its effect was also evaluated in this thesis. However, the main focus of this thesis is a new methodological approach to the research of depressive disorder. The main interest lies with the evaluation of automated monitoring of behaviour in this research. The first aim of this thesis was to evaluate the antidepressant effect of ketamine in the forced swimming test using software enabling automated monitoring of behaviour. The second aim was to meassure the change in phosphorylated Mammalian target of rapamycin (mTOR), using Enzyme-Linked ImmunoSorbent Assay (ELISA). The last, but the most important aim of this thesis was to implement the utilization of Phenotyper boxes in the automated behavioural evaluation of the olfactory bulbectomy model of depressive disorder and also evaluate the effect of ketamine in this model. Ketamine did not show an antidepressant effect in forced swimming test, however this observation could be influenced by chosen dose and mouse strain. Sensitivity of the test to chosen experimental protocol shows insufficient validity of this test. Observed change in level of phosphorylated mTOR corresponded with the behavioural results. Data collected from Phenotyper...
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Biological significance of neuroactive steroids in animal models of brain diseases
Rambousek, Lukáš ; Valeš, Karel (advisor) ; Votava, Martin (referee) ; Chvátal, Alexandr (referee)
Neurosteroids play an important role in the brain physiology and pathophysiology. They control inhibitory and excitatory neurotransmission. The presented thesis aims to investigate the biological significance of neuroactive steroid 3_5_-pregnanolone glutamate (3_5_P-Glu). We investigate the effect of 3_5_P-Glu in naïve rats. Next, we evaluate the effects of 3_5_P-Glu in animal model of schizophrenia and excitotoxic lesion of hippocampus induced by N-methyl- D-aspartate (NMDA). Furthermore, we morphologically characterize the NMDA lesion model. 3_5_P-Glu did not induce significant psychotomimetic side effects such as hyperlocomotion, sensorimotor grating deficit or memory impairment. Next, 3_5_P-Glu showed dose dependent pro-cognitive effects in animal model of schizophrenia; however, it had no effect on hyperlocomotion in this model. 3_5_P-Glu also ameliorated spatial learning deficit of rats induces by NMDA lesion of hippocampi in the Carousel maze and had mild effect on NMDA induced damage of hippocampus when applied before. Additionally, the morphological analysis of hippocampal NMDA lesion revealed overexpression of NMDA receptor NR1 and NR2B and downregulation of GABAA receptor _5 subunits. The lesion was very conservative, did not spread to other structures and did not affect GABAergic...
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Antidepressant effect of ketamine
Revayová, Anna ; Valeš, Karel (advisor) ; Šóš, Peter (referee)
Ketamine is used as an anaesthetic mainly in veterinary medicine and paediatrics. Thirteen years ago, interest in ketamine as an antidepressant emerged. Ketamine as an antidepressant works rapidly and is also effective in the case of patients suffering from treatment resistant depression.The main disadvantage of ketamine as an antidepressant is its psychotomimetic effect. Ketamine is an antagonist of the NMDA receptor, which has an important influence in brain activity. Through antagonism of this receptor, a large amount of processes can be affected, for example levels of glutamate, excitotoxicity, or density of other receptors. In addition, ketamine probably also affects the D2 receptors, but its role in this is uncertain. Ketamine influences synaptic plasticity and its effect can be modulated by repeated application, co-application with other drugs and other methods. Also gender seems to play role in the effect of ketamine. The aim of this work is to summarise possible mechanisms of effect of ketamine, its effect on synaptic plasticity and also possibilities of modulation of its effect. This thesis mentions the most important studies concerning ketamine as an antidepressant and possible future directions of research. Keywords: major depressive disorder, ketamine, antidepressant, NMDA antagonism,...
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Effect of dizocilpine on behavioral strategies of rats in the place avoidance task
Antošová, Eliška ; Valeš, Karel (advisor) ; Frynta, Daniel (referee)
Non-competitive antagonists of NMDA receptors can induce psychomimetic effects - they can cause schizophrenia-like behavior in healthy volunteers. MK-801 is such an agent. It is often used to model schizophrenia-like behavior in experimental animals. On the other hand, non-competitive antagonists of NMDA receptors show antidepressant effects both in patients suffering from depression and in animal models. Currently, cognitive deficit is considered to be a crucial symptom of the schizophrenia. Cognitive coordination is a process distinguishing irrelevant and relevant stimuli. A disruption of this process could play a pivotal role in cognitive deficit in schizophrenia. Active Allothetic Place Avoidance task (AAPA) could be a useful tool to study this phenomenon. In this task an animal has to distinguish between two spatial (reference) frames, whereas one of them is irrelevant and the other is relevant. The aims of my diploma thesis were: to study 1) behavioral strategies of laboratory rats in AAPA task and 2) effect of MK-801 on behavioral strategies and cognitive efficiency of rats in this task. The rats demonstrated two different strategies in the AAPA task. The first strategy was an active avoidance of an aversive sector; the second one was "freezing" with minimal active movement on the arena. Application...
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The influence of the neuroactive steroids inhibiting NMDA receptors on behaviour
Chvojková, Markéta ; Valeš, Karel (advisor) ; Mareš, Pavel (referee)
The neuroactive steroid pregnanolone glutamate (Pg glu), a synthetic analogue of the naturally occurring pregnanolone sulfate (3alpha5betaS), has neuroprotective properties and a minimum of adverse effects. The subject of my thesis is the influence of selected structural modifications of the molecule Pg glu on biological effects. The first modification involves an increase of lipophilicity, the second involves the attachment of a positively charged group to C3. All these neuroactive steroids are use-dependent inhibitors of NMDA receptors. The first aim of this thesis was to determine the neuroprotective effectiveness of the neuroactive steroids chosen. The second aim was to explore the influence of selected neuroactive steroids on motor coordination, reflexes, anxiety and locomotor activity, as well as the effect of their high doses. The third aim was to create a battery of behavioural tests for screening the biological effects of analogues of Pg glu in laboratory rodents. The neuroprotective effects were evaluated in a model of excitotoxic damage of hippocampus in the rat on the basis of its behavioural consequences. The neuroprotective efficacy of androstane glutamate (And glu) and Pg glu was demonstrated. In the case of positively charged molecules, neuroprotective efficacy was not demonstrated....
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The effect of partial agonist of serotonin-1A receptor on cognitive functions in animal model of schizophrenia
Antošová, Eliška ; Valeš, Karel (advisor) ; Telenský, Petr (referee)
Serotoin is a neurotransmitter participating in regulation of many physiologic fuctions. Main serotogenous neurons can be found in nukleus raphe of the brain stem. Nucleus raphe inervates many areas of the brain including the cerebal cortex and hipocampus. These structures are important for controling of higher cognitive functions. 5HT1A receptor is one of many subtypes of serotonin receptors and its activation inhibits iniciating of the action potencials. 5HT1A receptor is expressed presynapticaly as an autorecpetor in nucleus raphe. Activation of 5HT1A receptors decreased the output of the serotonin in the target structures. This key position enables to regulate the serotonin level in the brain. 5HT1A receptor can be found also postsynapticaly as an heteroreceptor in the hippocampus and in the brain cortex, where it affects the output of many other neurotransmitters. Experimental studies indicate that affecting of the 5HT1A function can improve many neuropsychiatric disorders such as schizophrenia, anxiety, depresion and it can also moderate the congitive deficit. It is supposed that the activation of 5HT1A autoreceptors and the inhibition of 5HT1A heteroreceptors can positively affect the cognigtive abilities. It seems that 5TH1A autoreceptors are more sensible for pharmacologic influence. Thus in these...
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A neuroprotective effect of the 3α5β-pregnanolon glutamate in the animal model of ischemic brain injury
Kletečková, Lenka ; Valeš, Karel (advisor) ; Zach, Petr (referee)
The neuroactive steroid 3α5β-pregnanolon glutamate (3α5βP-Glu) is the synthetic analogue of a naturally-occurring 3α5β-pregnanolon sulfate. Both agents inhibit preferentially tonically activated NMDA receptors by a use-dependent mechanism. The aplication of 3α5βP-Glu could reduce the excitotoxic injury of the brain during ischemic conditions, in which plays role the excessive activation of NMDA receptors. The objectives of this study are to determine the effect of systemic aplication of 3α5βP-Glu on an oxygen saturation and a regional cerebral blood flow in the brain of laboratory rat. Subsequently to establish and critically evaluate the animal model of a global ischemic brain injury. Finally to test the neuroprotective potential of 3α5βP-Glu on cognitive funtions in this model. The oxygen saturation and regional cerebral blood flow were measured in the area of dorsal hippocampus. Both observed parametres were significantly increased after the application of3α5βP-Glu. These findings confirm the assumption that 3α5βP-Glu has a neuroprotective effect. The bilateral occlusions of arteriae carotis communis following placement of the rat into a hypoxic box has been utilized as a model of global ischemic brain injury. The aplication of 3α5βP-Glu increased significantly the rats survival. However,...
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